INTRODUCTION — The peripheral T cell lymphomas (PTCL) are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all non-Hodgkin lymphomas (NHLs) in adults [1]. Anaplastic large cell lymphoma, T/null cell type (ALCL) accounts for approximately 2 percent of adult NHL and is the second or third most common PTCL histology in adults depending on the series analyzed [2,3]. (See "Classification of hematopoietic neoplasms".)
Four distinct forms of ALCL are recognized based on clinical features and molecular characterization:
●Primary systemic ALCL, anaplastic lymphoma kinase positive (ALK-positive ALCL)
●Primary systemic ALCL, anaplastic lymphoma kinase negative (ALK-negative ALCL)
●Breast implant-associated ALCL (iALCL)
●Primary cutaneous ALCL (PC-ALCL)
The World Health Organization (WHO) classification recognizes ALK-positive ALCL as a distinct clinicopathologic entity associated with translocations involving the ALK gene located on chromosome 2 [4,5]. These ALK-positive tumors affect mainly children and young adults, have a male predominance, and confer a better prognosis than ALK-negative ALCL. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma", section on 'Prognosis'.)
The management of systemic ALCL (ALK-positive and ALK-negative) will be discussed here. The management of primary cutaneous ALCL and breast implant-associated ALCL are presented separately as is the diagnosis of ALCL.
●(See "Primary cutaneous anaplastic large cell lymphoma".)
●(See "Breast implant-associated anaplastic large cell lymphoma".)
PRETREATMENT EVALUATION — Pretreatment evaluation of the patient diagnosed with anaplastic large cell lymphoma (ALCL) must assess expression of ALK and CD30, establish the disease stage (table 1), assess performance status (table 2A-B), and determine the International Prognostic Index (IPI) score (table 3). (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma", section on 'Diagnosis'.)
REMISSION INDUCTION — Nearly all cases of ALCL express CD30, which can be targeted by brentuximab vedotin (BV; CD30-directed antibody linked to the antitubulin agent monomethyl auristatin E).
CD30-positive ALCL — For ALCL in which ≥10 percent of cells express CD30 by immunohistochemistry, we recommend initial treatment with BV+CHP (BV plus cyclophosphamide, doxorubicin, prednisone) rather than alternative chemotherapy regimens. This recommendation is based on superior survival without added toxicity when BV+CHP was compared with CHOP (CHP+vincristine).
We generally treat with BV+CHP every three weeks for six cycles; the BV+CHP regimen is similar to CHOP (table 4), but vincristine is excluded and, instead, BV 1.8 mg/kg is given intravenously on day 1 of each cycle. BV is approved by the US Food and Drug Administration (FDA) for treatment of CD30-positive PTCL [6]. The dose of BV should be adjusted for mild hepatic impairment, and prescribing information carries a warning about the rare occurrence of progressive multifocal leukoencephalopathy. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
Our preference for BV+CHP is based on superior overall survival (OS) and progression-free survival (PFS) without added toxicity among 452 patients with CD30-positive tumors (70 percent with ALCL) who were randomly assigned to BV+CHP versus CHOP in the multicenter, double-blind, ECHELON-2 trial [7]. Median PFS was 48.2 months (95% CI 35.2 to not evaluable) in the BV+CHP group and 20.8 months (12.7 to 47.6) in the CHOP group (hazard ratio 0.71; 95% CI 0.54-0.93). This trial was not powered to compare efficacy between individual histological subtypes, but a PFS advantage for BV+CHP was seen for both ALK-positive and ALK-negative ALCL. BV+CHP was associated with more grade ≥3 diarrhea (6 versus 1 percent), but rates of other grade ≥3 toxicities were similar: neutropenia (35 percent), peripheral sensory neuropathy (4 percent), and nausea (2 percent). Adverse events leading to death occurred in 3 and 4 percent of patients treated with BV+CHP and CHOP, respectively.
CD30-negative ALCL — For ALCL in which CD30 is expressed by <10 percent of tumor cells, we suggest treatment with an anthracycline-based chemotherapy regimen that is selected based on age, medical fitness, and clinician/patient preference:
●For patients >60 years old or for less medically fit individuals of any age, we favor CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (table 4) to avoid the increased toxicity with other regimens.
●For patients ≤60 years old, we suggest treatment with CHOEP (CHOP plus etoposide) rather than CHOP (table 4) or other more intensive regimens. This preference places greater value on improvements in clinical outcome than on increased toxicity with CHOEP, when compared to CHOP. Compared with CHOEP, more intensive induction regimens (eg, infusional EPOCH, HyperCVAD) provide comparable clinical outcomes but greater toxicity.
CHOP is generally administered every three weeks (table 4). For CHOEP, intravenous etoposide (100 mg/m2) is administered on days 1 through 3 of each 21-day cycle in addition to standard CHOP. Alternatively, standard CHOP may be administered with intravenous etoposide (100 mg/m2) on day 1 followed by oral etoposide (200 mg/m2) on days 2 and 3 of each 21-day cycle. There is no evidence that dose intensification or more frequent administration (eg, every two weeks) of CHOP or CHOEP provides a benefit [8,9]. If infusional EPOCH is selected, it should be administered without rituximab (table 5).
For patients treated with an anthracycline-based regimens, estimated five-year OS is generally superior for patients with ALK-positive ALCL (70 to 93 percent) than for patients with ALK-negative ALCL (15 to 49 percent) [8,10-16]. As an example, in a retrospective analysis by the German High-Grade NHL Study Group, 191 patients with ALCL (78 ALK-positive, 113 ALK-negative) were treated with an anthracycline-based regimen [8]. Addition of etoposide to CHOP was associated with improved event-free survival (EFS) but no difference in OS; for patients with ALK-positive ALCL, EFS and OS were 76 and 90 percent, respectively, while for patients with ALK-negative ALCL, EFS and OS were 46 and 62 percent, respectively.
Is there a role for radiation? — For most patients with limited (stage I/II) ALCL (table 1), we suggest six cycles of anthracycline-based chemotherapy rather than an abbreviated course of chemotherapy followed by radiation therapy (RT) (algorithm 1). If a patient with limited stage ALCL is unable to tolerate chemotherapy or has significant comorbidities, then three or four cycles of chemotherapy followed by RT is an acceptable alternative. There is no evidence that adding RT after six cycles of therapy is beneficial for patients who achieve a CR. We do offer RT to patients who achieve a partial response (PR) with six cycles of chemotherapy with a goal of achieving CR.
No large, randomized trial has definitively evaluated the efficacy of RT in conjunction with chemotherapy in early stage ALCL. The following small, non-randomized studies have evaluated radiation in this setting:
●An analysis of the Swedish Lymphoma Registry evaluated the effect of RT as consolidation following chemotherapy in 118 patients with stage I/II T cell lymphoma (data for ALCL were not analyzed separately) [9]. Thirty-two of these patients received local RT to a median dose of 40 Gy. Although there was a trend toward superior OS and PFS in patients who underwent RT, the difference was not statistically significant. On subset analysis, the 12 patients who responded to three or four cycles of CHOP or CHOEP and then underwent RT had identical outcomes when compared with early stage patients who received at least six cycles of the same chemotherapy. The small number of patients who received abbreviated chemotherapy plus RT limits the interpretation of this analysis.
●Another study analyzed the outcome of 46 adult patients with stage I or stage II systemic ALCL all but two of whom received CHOP or a CHOP-like regimen followed by RT [17]. The five-year OS and PFS for stage I disease were 95 and 77 percent respectively, while for stage II disease the OS and PFS were 75 and 52 percent respectively.
●A third retrospective study that included patients with ALCL showed no benefit to RT in early stage disease following at least six cycles of anthracycline-based chemotherapy [18]. Patients who received three or four cycles of chemotherapy with involved-field RT had a similar outcome to patients treated with six or more courses of chemotherapy alone.
Response assessment — One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response to treatment should be documented by history, physical examination, and laboratory studies (complete blood count, lactate dehydrogenase, and biochemical profile). The post-treatment imaging study of choice is the positron emission tomography/computed tomography (PET/CT) scan, which provides information on the size and activity of residual masses and allows for the distinction between active disease and fibrosis. PET/CT should be obtained six to eight weeks after completion of chemotherapy and 12 weeks after the completion of RT [19].
Disease response is determined using information gathered from the history, physical, and PET/CT scan (table 6).
If a partial remission is obtained, consolidation RT may be considered for patients with localized disease who are not candidates for transplantation. Otherwise, patients with a partial remission are frequently considered for second-line chemotherapy agents and/or transplantation. (See 'Relapsed or refractory disease' below.)
Autologous HCT in first remission — The poor outcomes in certain subgroups of patients with ALCL after conventional chemotherapy alone have generated interest in the use of high-dose chemotherapy and autologous HCT (rescue) as consolidation therapy in first CR. The role of consolidation therapy in ALCL is controversial. The decision to proceed to autologous HCT must take into account the patient's age, International Prognostic Index (IPI) (table 3), and ALK status, as well as comorbidities that might impact eligibility (algorithm 1). (See "Determining eligibility for autologous hematopoietic cell transplantation".)
●ALK-positive ALCL – For patients with ALK-positive ALCL, our decision to offer HCT depends largely on age and IPI score. We offer HCT to patients >40 years of age with a IPI score ≥3. With chemotherapy alone, fewer than half of such patients will survive five years [11]. In contrast, we do not offer HCT in first CR to patients with ALK-positive ALCL with an IPI <3 or to those <40 years of age regardless of IPI given their more favorable prognosis (estimated OS 70 to 90 percent at five years).
●ALK-negative ALCL – Patients with ALK-negative ALCL generally have a worse prognosis than patients with ALK-positive disease and require more intensive therapy. The exception is patients with an IPI <2. If a patient with an IPI score <2 enters a CR following induction chemotherapy, the risks and benefits of HCT should be discussed. In general we favor observation for most patients in this subgroup, particularly those over the age of 65 that may have increased toxicity with HCT. In contrast, we usually offer HCT to patients with ALK-negative ALCL with an IPI ≥3.
No randomized trials have compared standard chemotherapy alone versus chemotherapy followed by autologous HCT in first remission in patients with ALCL. Data regarding HCT largely come from small non-randomized prospective trials and retrospective analyses:
●A prospective, non-randomized trial by the Nordic Lymphoma Group reported outcomes following autologous HCT in first remission in 160 patients with a confirmed diagnosis of T cell lymphoma (31 with ALK-negative ALCL) [18]. Patients with ALK-positive ALCL were excluded. Induction therapy consisted of CHOP for patients over the age of 60 and CHOEP for those under 60. Responding patients underwent HCT following BEAM conditioning. Patients with ALCL had estimated five-year OS of 70 percent and PFS of 61 percent. These PFS and OS rates were superior to those of other T cell lymphoma histologies.
●In a second study of HCT for newly diagnosed aggressive lymphoma, all 15 patients with ALCL achieved a CR and there were no relapses after a follow-up of more than five years [20]. The EFS and OS rates at five years were both 87 percent and were superior to historical controls based on patient age-adjusted IPI (71 and 69 percent, respectively). However, 7 of the 15 patients were ALK-positive and may have done well even without HCT.
Other small, uncontrolled prospective trials have evaluated the use of HCT in first CR for patients with ALCL [20-22]. Although they have demonstrated promising results, issues of selection bias and the lack of a randomized control group limit the interpretation of these trials and the ability to generalize their results. In addition, these studies included patients with ALK-positive ALCL that are known to have an excellent prognosis with induction chemotherapy alone.
SURVEILLANCE FOR RELAPSE — Following the completion of therapy, restaging, and documentation of complete response, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends upon the comfort of both the patient and physician. When planning the post-treatment surveillance strategy, care should be taken to limit the number of computed tomography (CT) scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)
Our approach to patient surveillance is to schedule patient visits every three months during the first two years, then every six months starting two years after complete response. Starting at year 5, patients are seen once per year. At these visits we perform a history and physical examination, complete blood count, chemistries, and lactate dehydrogenase. We obtain a CT scan of the chest, abdomen, and pelvis every six months for the first 18 months after documentation of an initial complete response. We only obtain additional positron emission tomography/computed tomography (PET/CT) scans to further evaluate any concerning findings noted on CT scans. We do not obtain routine CT scans after 18 months unless there are signs, symptoms, or exam findings to suggest relapse.
Relapsed disease can be suggested by changes on imaging studies but can only be confirmed by biopsy. As such, a biopsy should always be obtained to document relapsed disease before proceeding to salvage therapy.
RELAPSED OR REFRACTORY DISEASE
Our approach — Management of patients with relapsed or refractory ALCL is largely based on whether the patient is a candidate for autologous or allogeneic hematopoietic cell transplantation (HCT). (See "Determining eligibility for autologous hematopoietic cell transplantation" and "Determining eligibility for allogeneic hematopoietic cell transplantation".)
We suggest autologous HCT for relapsed or refractory systemic ALCL, rather than alternative approaches. Autologous HCT provides a benefit to patients with relapsed ALK-positive ALCL and, to a lesser extent, patients with relapsed ALK-negative ALCL. A subset of these patients will achieve long-term disease control. Therefore, if a patient is medically suitable for transplant, the intent of subsequent treatment should be to attain a complete remission (CR) in preparation for autologous HCT.
Autologous HCT has not been directly compared with other approaches in this setting. Some patients treated with brentuximab vedotin (BV) alone have maintained long-term CR without subsequent therapy, but it is not yet clear if autologous HCT improves long-term survival in patients who have a CR after BV treatment. Several reports have described successful allogeneic HCT for ALCL [23,24], but we favor autologous HCT in the setting of a chemotherapy-sensitive relapse because of its more favorable toxicity profile. If a patient has had a prior autologous HCT, then allogeneic HCT is the preferred transplant strategy.
Patients who are not candidates for transplant are treated with palliative intent, generally with sequential single agents or combination therapies with comparatively low toxicity.
Transplant-eligible patients
Following initial chemotherapy — A number of chemotherapy agents and combination regimens have been used for patients with resistant or relapsed ALCL. Given the rarity of ALCL, randomized trials are not available to guide the selection of therapy. As such, a choice among regimens is largely based on side effect profiles and clinical experience. We use the following step-wise approach aimed at achieving a CR prior to proceeding with HCT:
●Brentuximab vedotin – Brentuximab vedotin (BV) is our preferred second-line therapy for ALCL that relapses ≥6 months from last treatment with BV and for patients with refractory ALCL who did not receive BV during induction therapy. The preference for BV is based on the high response rate, sustained long-term remissions in a subset of patients, reasonable toxicity profile, and outpatient mode of administration. Although data are scant, it is not clear if patients who achieve a CR with BV have a superior progression-free survival (PFS) when consolidated with transplant. The optimal number of cycles of BV prior to transplant is unclear. We generally treat for two to three cycles beyond CR in preparation for transplant. (See 'Brentuximab vedotin' below.)
●Combination chemotherapy – For patients who do not respond to BV or have a partial response (PR) with BV, we favor subsequent treatment with combination chemotherapy. Our preferred regimen is GDP (gemcitabine, dexamethasone, cisplatin) given its non-inferiority and favorable toxicity profile compared with DHAP (dexamethasone, high-dose cytarabine, cisplatin), and the fact that GDP can be administered as an outpatient. Patients who achieve a CR with this regimen should be consolidated with an autologous HCT, while those with a PR should be considered for allogeneic HCT or additional salvage therapy. (See 'Combination salvage regimens' below.)
●Sequential salvage therapies – For patients who do not respond to BV or GDP, subsequent therapy is palliative in most circumstances. The small group of patients who achieve a subsequent CR with additional treatment and are appropriate candidates can be considered for allogeneic HCT but most will receive sequential salvage therapies with palliative intent. For patients with ALK-positive ALCL, we favor ceritinib or crizotinib in this setting. For patients with ALK-negative ALCL, pralatrexate, romidepsin, and belinostat are all reasonable considerations with choice of therapy based on expected toxicity profile, patient comorbidities, and prior treatment. (See 'ALK inhibitors' below and 'Other agents' below.)
Following autologous HCT — Patients who relapse after receiving an autologous HCT are offered further chemotherapy. We also favor BV vedotin in this setting with GDP (gemcitabine, dexamethasone, cisplatin) as the preferred next option (if not received pretransplant) for patients who do not respond to BV. (See 'Brentuximab vedotin' below and 'Combination salvage regimens' below.)
The decision to proceed with allogeneic HCT is complicated and must take into account the response to therapy, the patient's comorbidities, and the ALK status of the tumor.
●ALK-negative ALCL – We offer allogeneic HCT to patients with ALK-negative ALCL who achieve a CR or PR. However, the risks and benefits of this approach must be carefully discussed with the patient. Allogeneic HCT is associated with a significant risk of early morbidity and late complications but offers the opportunity for long-term remission. Although the experience is limited, long-term remissions have also been described with BV. (See 'Allogeneic HCT' below.)
●ALK-positive ALCL – The decision to proceed to allogeneic HCT after BV is more difficult in patients with ALK-positive ALCL given the high response rates and durable responses observed with ALK inhibitors (ie, crizotinib and ceritinib). In this setting, we often treat with BV until loss of response or toxicity with plans to use an ALK inhibitor at relapse. Allogeneic HCT is usually reserved for use following treatment with an ALK inhibitor. (See 'ALK inhibitors' below.)
Patients who do not respond to the above agents are generally treated with palliative intent with sequential pralatrexate, romidepsin, and/or belinostat. If patients achieve a PR or CR with one of these agents, allogeneic HCT can be considered.
Relapse after allogeneic HCT — The treatment approach for recurrences after allogeneic HCT is similar to the approach utilized in patients who recur after autologous HCT, though treatment is much more likely to be palliative in this setting. Patients who respond to treatment can be considered for donor lymphocyte infusion, which can result in long-term remissions in a small subgroup of patients. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation".)
Transplant-ineligible patients — Although long-term remissions are described with both brentuximab vedotin (BV) and ALK inhibitors, treatment of relapsed or refractory disease in patients ineligible for transplant should largely be considered palliative.
●Brentuximab vedotin – For patients who have not received prior BV, we favor this agent given a high response rate, outpatient administration, and ability to continue treatment indefinitely. Peripheral neuropathy is typically the biggest barrier to long-term administration and can occasionally be mitigated by dose reduction and/or increasing the interval between treatments. If patients discontinue BV while responding, retreatment is reasonable if the duration of response was greater than six months and there are no toxicities that preclude further administration. (See 'Brentuximab vedotin' below.)
●ALK inhibitors – Patients with ALK-positive ALCL that do not respond to BV should be offered crizotinib or ceritinib. Although only small numbers of patients have been treated with these agents, response rates are high and the durability of responses has been excellent. Both drugs also have favorable toxicity profiles and the convenience of oral administration. We generally use sequential therapy starting with crizotinib and reserving ceritinib for crizotinib failures since ceritinib has demonstrated activity in patients with ALK rearranged lung cancers that have progressed on crizotinib. (See 'ALK inhibitors' below.)
●Other agents – For patients with ALK-negative ALCL who progress on or are intolerant of BV or patients with ALK-positive ALCL that have progressed on or are intolerant of both BV and at least one ALK inhibitor, there are a variety of palliative options including single agent gemcitabine, gemcitabine in combination with either cisplatin or oxaliplatin, pralatrexate, romidepsin, or belinostat. (See 'Other agents' below.)
Other agents that have shown activity in ALCL but are not approved by the US Food and Drug Administration for this indication include bendamustine [25] and lenalidomide [26].
Efficacy of second-line agents
Brentuximab vedotin — Brentuximab vedotin (BV) is an antibody drug conjugate composed of a CD30-directed antibody linked to the antitubulin agent monomethyl auristatin E. Treatment of relapsed or refractory systemic ALCL with BV achieves CR in about half of patients, plus additional PRs. BV alone has the potential to induce long-term remissions in a subset of patients without any further anticancer therapy or HCT, as described below.
BV is generally well tolerated, but serious side effects can occur. Infusion reactions are uncommon, but anaphylaxis has been reported, and infections, cytopenias, gastrointestinal complications (eg, hemorrhage, perforation, obstruction), and other adverse effects have been reported [27]. Progressive multifocal leukoencephalopathy is a rare complication of BV treatment and typically presents with subacute neurologic deficits, which may include altered mental status, visual symptoms, weakness, ataxia, and seizures [28]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
BV is approved by the US Food and Drug Administration for the treatment of patients with systemic ALCL after failure of at least one prior multiagent chemotherapy regimen [27].
Examples of studies of BV in relapsed ALCL include:
●In a phase II multicenter trial, 58 patients with relapsed or refractory systemic ALCL were treated with BV (1.8 mg/kg every three weeks for up to 16 cycles) [28]. The overall response rate (ORR) was 86 percent (57 percent CR) with median time to objective response and CR of 6 and 12 weeks, respectively; the median duration of response following CR was 13 months. The most common severe (grade 3/4) side effects were neutropenia (21 percent), thrombocytopenia (10 percent), and peripheral sensory neuropathy (10 percent).
After more than five years of follow up, 14 percent of the patients treated with BV alone remained in sustained CR without autologous HCT or any other new anticancer treatment [29]. The median OS for the entire cohort was not reached and no patient experienced disease progression beyond 40 months after treatment. Among the 38 patients who achieved CR, 16 later underwent autologous hematopoietic cell transplantation (HCT). At present, it is not clear if autologous transplant improves long-term survival in patients who have a CR after treatment with BV.
●A retrospective observational study of 40 patients with relapsed/refractory ALCL reported 63 percent ORR (45 percent CR) and 54 percent disease-free survival at 24 months [30]. Best response was observed after a median of four cycles in most patients. Treatment was well tolerated and no deaths were linked to drug toxicity.
Combination salvage regimens — Traditionally, the following regimens utilized in relapsed/refractory aggressive B cell malignancies are also used in ALCL:
●GDP (gemcitabine, dexamethasone, cisplatin) [31,32] – Gemcitabine (1000 mg/m2 per day on days 1 and 8), cisplatin (75 mg/m2 on day 1), and oral dexamethasone (40 mg daily on days 1 through 4) are administered at 21-day intervals. Hematologic toxicity is universal. Febrile neutropenia is seen in approximately 15 percent of patients.
●DHAP (dexamethasone, high-dose cytarabine, cisplatin) [33,34] – Hematologic toxicity is universal with most patients requiring transfusion of blood products. Severe (grade 3/4) nonhematologic side effects include infection (24 percent) and nephrotoxicity (6 percent).
●ICE (ifosfamide, carboplatin, etoposide) [35-37] – Hematologic toxicity is universal with approximately one-third of patients requiring transfusion of blood products. Severe (grade 3/4) nonhematologic side effects include infection (23 percent) and nephrotoxicity (1 percent).
We prefer the use of GDP for most patients given its non-inferiority and favorable toxicity profile compared with DHAP, and the fact that GDP can be administered as an outpatient. The following studies have evaluated these three regimens in aggressive non-Hodgkin lymphoma:
●A randomized study comparing DHAP to GDP in patients with relapsed/refractory aggressive lymphomas included 65 patients with peripheral T cell lymphoma (PTCL), 23 of whom had ALCL [32]. Rituximab was added to each regimen for patients with B cell lymphomas. For the intention-to-treat population, when compared with DHAP, GDP resulted in a similar response rate (45 versus 44 percent) and transplantation rate (52 versus 49 percent), and no difference in event-free survival (EFS) or overall survival (OS) at a median follow-up of 53 months. GDP was less toxic than DHAP with a significant decrease in the need for platelet transfusion and need for hospitalization due to toxicity. Patients in the GDP arm also reported a better quality of life compared with patients receiving DHAP. Although patients with PTCL were not analyzed separately, the protocol did meet its primary endpoint establishing the non-inferiority of GDP compared with DHAP.
●The CORAL trial established the equivalence of RICE to RDHAP in aggressive B cell lymphomas, and we feel it is reasonable to conclude that ICE and GDP are likely to have equivalent efficacy in relapsed/refractory aggressive lymphomas [38]. We favor GDP because the regimen can be given as an outpatient. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients".)
There are potential concerns regarding the nephrotoxicity and ototoxicity of cisplatin and therefore an interest in substituting other platinum compounds, particularly oxaliplatin, for cisplatin. The combination of dexamethasone, gemcitabine, and oxaliplatin has not been compared with GDP in randomized trials and there are no data specific to ALCL. In one study of dexamethasone, oxaliplatin, and gemcitabine in PTCL, the ORR was 38 percent (8 percent complete) [39].
ALK inhibitors — There is a paucity of data regarding the efficacy of ALK inhibitors in patients with ALK-positive ALCL. Case reports and small case series of crizotinib and ceritinib have demonstrated high response rates and durable responses in small numbers of heavily pretreated ALK-positive ALCL. Both drugs also have favorable toxicity profiles and the convenience of oral administration. However, neither of these drugs is approved by the US Food and Drug Administration for this indication, and there are no studies comparing the efficacy of ALK inhibitors to other agents used in ALCL, particularly BV.
Details regarding the side effects of ALK inhibitors in patients with lung cancer are discussed in more detail separately. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
Crizotinib — The following reports have illustrated the efficacy of crizotinib in ALK-positive ALCL:
●In one report, two patients with relapsed/refractory ALK-positive ALCL experienced dramatic responses with clinical improvement occurring within eight days in one instance [40].
●In a follow-up study, responses were seen in 9 of 11 patients with heavily pretreated ALK-positive ALCL (median of three prior therapies, some including transplant), with clinical evidence of benefit occurring as early as 12 days after the initiation of crizotinib [41]. The estimated PFS and OS rates at two years were 64 and 73 percent, respectively. There seemed to be a plateau in the PFS curve starting as early as two months, and one response of over 40 months was ongoing at the time of the report. Two relapses had identifiable ALK mutations likely conferring resistance.
●Similar results were seen in a trial of crizotinib in 14 patients with heavily pretreated ALK-positive ALCL (median of three prior treatments, some including transplant) [42]. While follow-up continues, at a median duration of treatment of 33 weeks, there were four PRs and five CRs (ORR of 64 percent).
The optimal length of treatment (months, years, life-long) has not been established, but common practice is to continue treatment until progressive disease or unacceptable adverse events. There have been case reports of abrupt relapse following discontinuation of crizotinib [43].
Ceritinib — The ALK inhibitor ceritinib is more potent than crizotinib in vitro and has demonstrated responses in patients with ALK rearranged lung cancer that progressed on crizotinib. Three patients with ALK-positive ALCL were included on the ASCEND-1 trial evaluating the efficacy of ceritinib in patients with ALK rearranged tumors [44]. Two of the three patients with ALCL achieved a CR while one had a PR with 95 percent reduction in tumor size. All responses were ongoing at the time of the report with duration of response ranging from ≥20 months to ≥26 months.
Other agents — Pralatrexate, romidepsin, and belinostat are all approved by the US Food and Drug Administration to treat relapsed/refractory PTCL. None have clear preferential activity in ALCL, and the selection of agents should be based on comorbidities and prior therapy. The use of these drugs is described in more detail separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)
Transplantation for relapsed/refractory ALCL
Autologous versus allogeneic HCT — Allogeneic HCT and autologous HCT offer a chance of long-term survival to patients with relapsed or refractory ALCL who have a response to second-line chemotherapy. Patients who achieve a CR before transplant have a higher chance of long-term survival. Decisions regarding transplant eligibility should be made on a case-by-case basis based on a risk-benefit assessment and the needs and wishes of the patient. This is discussed in more detail separately. (See "Determining eligibility for autologous hematopoietic cell transplantation" and "Determining eligibility for allogeneic hematopoietic cell transplantation".)
For medically fit patients, the choice between allogeneic HCT and autologous HCT depends on the response to second-line chemotherapy and whether the patient received an autologous HCT as consolidation in first CR:
●For patients who have not undergone a prior autologous HCT and who achieve a CR with salvage chemotherapy, we suggest autologous HCT rather than allogeneic HCT.
●For patients who have undergone a prior autologous HCT, have a PR with second-line therapy, or require several therapies at relapse to achieve a CR, we favor allogeneic HCT given the likely intrinsic chemoresistance of the disease in these instances. There is no evidence to suggest that myeloablative conditioning is superior to reduced-intensity allogeneic HCT, and we favor reduced-intensity conditioning in most circumstances.
Support for this approach comes from retrospective analyses and non-randomized prospective trials of highly selected patients described below. As an example, an analysis of the Center for International Blood and Marrow Transplantation Research (CIBMTR) database identified 112 patients with ALCL who had undergone autologous HCT (61 patients) or allogeneic HCT (50 patients) at various phases of the disease [45]. Autologous HCT was associated with superior PFS (55 versus 35 percent) and OS (68 versus 41 percent), with significantly less non-relapse mortality. An analysis that excluded those who underwent HCT in first CR confirmed the higher rate of three-year OS (62 versus 33 percent) and lower transplantation-related mortality (5 versus 32 percent), with no difference in PFS or relapse/progression.
Autologous HCT — Autologous HCT is frequently incorporated into the initial treatment of patients with ALCL as consolidation therapy after initial combination chemotherapy. Autologous HCT appears to be less effective in the treatment of relapsed or refractory disease, except perhaps for ALK-positive ALCL [46]. When compared with patients transplanted in first CR, OS and PFS rates are significantly lower when autologous HCT is performed on patients in subsequent CR, PR, or those with progressive disease.
The following are examples of the prospective and retrospective studies that have investigated autologous HCT for relapsed or refractory PTCL, including ALCL:
●A retrospective series of 28 patients transplanted for relapsed PTCL reported a three-year OS rate of 69 percent [47]. Among those with ALCL, three-year OS was 86 percent overall and was higher for those with ALK-positive ALCL versus ALK-negative ALCL (100 versus 0 percent).
●An analysis performed by the European Group for Blood and Marrow Transplantation evaluated 64 adult and pediatric patients (median age 25 years) who underwent autologous HCT for ALCL in CR (47 percent), PR (28 percent), or with more advanced/chemotherapy refractory disease (25 percent) [48]. Relapse or progression was lower for those transplanted in first CR (1 of the 15 patients) than for those transplanted in a subsequent CR (6 of 15 patients), in PR (6 of 18 patients), or in a relapsed or refractory disease state (14 of 16 patients). Actuarial OS at 10 years was 70 percent. Multivariate analysis revealed superior outcomes for patients with the following characteristics: CR at transplant, younger age, absence of B symptoms, and lack of extranodal disease.
●In an analysis of the CIBMTR database of 39 patients with ALCL undergoing autologous HCT beyond first CR had one-year and three-year PFS rates of 53 and 50 percent, and one-year and three-year OS rates of 74 and 65 percent, respectively [45].
●In a trial of 15 patients with ALK-negative ALCL undergoing autologous HCT, 13 patients relapsed after transplant and the median PFS was 12 weeks with a median OS was 72 weeks [49].
Allogeneic HCT — Allogeneic HCT has been studied in a selective group of patients with relapsed or refractory PTCL, including ALCL. Rates of OS at five years post-transplant are approximately 50 to 60 percent, with non-relapse mortality (NRM) rates of 20 to 25 percent.
Small, uncontrolled prospective trials and retrospective analyses have investigated the use of allogeneic HCT in PTCL, including ALCL:
●An uncontrolled prospective trial of 17 patients with relapsed or refractory PTCL who underwent reduced-intensity allogeneic HCT from a sibling or matched unrelated donor reported five-year PFS and OS rates of 49 and 54 percent, respectively [50]. At a median follow-up from enrollment of 28 months, 14 patients were still alive, two patients had died of progressive disease, and one had died with sepsis.
●In an uncontrolled prospective trial of nonmyeloablative allogeneic HCT in 17 patients with T cell or NK cell non-Hodgkin lymphoma (relapsed, refractory, or in first CR), estimated rates of OS and PFS at three years were 59 and 53 percent with a median follow-up 3.3 years [51]. Estimated rates of NRM and relapse at three years were 19 and 26 percent, respectively.
●In a single-center retrospective analysis of 52 patients with relapsed, refractory, or newly diagnosed PTCL or advanced mycosis fungoides/Sézary syndrome who underwent myeloablative (60 percent) or reduced-intensity allogeneic HCT, PFS and OS at three years were 30 and 41 percent, respectively [52]. When compared with reduced-intensity regimens, myeloablative regimens were associated with higher NRM (36 versus 14 percent at three years) and lower relapse rates, resulting in similar survival. When compared with predominantly extranodal histologies (eg, NK/T cell lymphoma, cutaneous lymphomas), patients with predominantly nodal histologies (including ALCL) had superior PFS (45 versus 6 percent) and OS (52 versus 23 percent) at three years. At a median follow-up of 49 months, there appeared to be a plateau in the survival curves suggesting possible cure of a subset of patients.
●Fifteen of 160 patients who participated in two pivotal phase 2 studies of BV underwent a subsequent allogeneic HCT [23]. The estimated two-year PFS rate was 66 percent, and the median PFS had not been reached at the time of the analysis. Eleven of the 15 patients were alive and the estimated two-year OS was 80 percent.
Together, these studies suggest that some patients with relapsed or refractory PTCL who undergo allogeneic HCT will achieve long-term disease control.
SPECIAL POPULATIONS — The general treatment principles for ALCL apply to most disease presentations and patient populations. Two important presentations that require special consideration are breast implant-associated ALCL (iALCL) and primary cutaneous ALCL (PC-ALCL).
Primary cutaneous ALCL — Primary cutaneous ALCL (PC-ALCL) is a rare and generally indolent disease that can occur in the context of or be confused with lymphomatoid papulosis (LyP) or transformed mycosis fungoides. The key to treatment of PC-ALCL is often to avoid overtreatment. Oncologists unfamiliar with the disease may recommend aggressive systemic chemotherapy including high-dose chemotherapy and autologous stem cell transplantation when such steps are unnecessary and overly toxic. (See "Primary cutaneous anaplastic large cell lymphoma".)
Breast implant-associated ALCL — Breast implant-associated ALCL is a rare but increasingly well-described entity. The malignant cells are confined to the fluid within the capsule surrounding the implant can be managed with capsulectomy followed by observation. This approach is not appropriate if there is a mass lesion. (See "Breast implant-associated anaplastic large cell lymphoma".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SUMMARY AND RECOMMENDATIONS
●Description – Systemic anaplastic large cell lymphoma (sALCL) is among the more common T cell lymphomas and includes:
•Anaplastic lymphoma kinase (ALK)-positive sALCL
•ALK-negative sALCL
Breast implant-associated ALCL and primary cutaneous ALCL are distinct disorders that are discussed separately. (See "Breast implant-associated anaplastic large cell lymphoma" and "Primary cutaneous anaplastic large cell lymphoma".)
●Pretreatment evaluation – Evaluation includes determination of ALK status, disease staging (table 1), performance status (table 7), and International Prognostic Index (IPI) score (table 3).
●Approach – For all patients with sALCL, we perform positron emission tomography (PET)/computed tomography (CT) after three cycles of chemotherapy (PET3). Response is judged by five-point (Deauville) scale (table 8), according to Lugano criteria (table 6).
For patients with no response or progressive disease on PET3, we obtain biopsy confirmation, if feasible. If biopsy confirms sALCL, we treat as relapsed/refractory sALCL. (See 'Relapsed or refractory disease' above.)
•Preferred chemotherapy regimen – For ALK-positive or ALK-negative sALCL of any stage, we recommend treatment with six cycles of BV+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone), rather than six cycles of CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) (Grade 1B).
For patients with limited stage (stage I or II) sALCL who are medically-unfit or tolerate BV+CHP poorly, three cycles of BV+CHP followed by RT is an acceptable alternative.
•End of treatment response – PET/CT is repeated after completing planned therapy.
-Complete response (CR) – For patients with CR (Deauville 1 to 3), we stratify post-remission management according to ALK status (below).
-Less than CR – For less than CR (Deauville 4 or 5), we treat for relapsed/refractory disease. (See 'Relapsed or refractory disease' above.)
•Post-remission management – Guided by ALK status:
-ALK-negative – We suggest consolidation with autologous hematopoietic cell transplantation (HCT), rather than observation (Grade 2C).
-ALK-positive – We suggest observation, rather than autologous HCT (Grade 2C).
●Monitoring – Surveillance for relapse and treatment-related adverse effects (AEs) is described above. (See 'Surveillance for relapse' above.)
●Relapsed/refractory (r/r) sALCL – Management varies according to prior treatment, fitness, and ALK status. (See 'Relapsed or refractory disease' above.)
•Medically-fit – Guided by prior therapy:
-No prior autologous HCT – We suggest autologous HCT, rather than salvage chemotherapy (Grade 2C).
-Prior autologous HCT – We offer allogeneic HCT if a suitable donor is available; otherwise, we treat with chemotherapy.
•Less-fit – We treat with salvage chemotherapy or symptomatic/palliative management, according to patient preference.
●Salvage chemotherapy – Choice of salvage therapy is informed by prior therapy:
•No prior BV – Treat with single-agent BV.
•Prior BV – We favor salvage treatment with GDP (gemcitabine, dexamethasone, cisplatin), but some experts favor DHAP (dexamethasone, high-dose cytarabine, cisplatin) or ICE (ifosfamide, carboplatin, etoposide).
Other options include an ALK inhibitor (eg, crizotinib, ceritinib) for patients with ALK-positive disease or pralatrexate, romidepsin, or belinostat for ALK-positive or negative sALCL.
